The Oxygen Dissociation Curve of Blood in COVID-19

COVID-19 hinders oxygen transport to the consuming tissues by at least 2 mechanisms: In the injured lung saturation of hemoglobin is compromised, in the tissues an associated anemia reduces the volume of delivered oxygen. For the first problem increased hemoglobin oxygen affinity (left shift of the oxygen dissociation curve ODC) is of advantage, for the 2nd, however, the contrary is the case. Indeed a right shift of the ODC has been found in former studies for anemia caused by reduced cell production or hemolysis. This resulted from increased 2,3-biphosphglycerate (2,3-BPG) concentration. In 3 investigations in COVID-19, however, no change of hemoglobin affinity was detected in spite of probably high [2,3-BPG]. The most plausible cause for this finding is formation of methemoglobin, which increases the oxygen affinity and thus apparently compensates for the 2,3-BPG effect. But this "useful effect" is cancelled by the concomitant reduction of functional hemoglobin. In the largest study on COVID-19 even a clear left shift of the ODC was detected when calculated from measurements in fresh blood rather than after equilibration with gases outside the body. This additional „in vivo" left shift possibly results from various factors (e. g. concentration changes of Cl-, 2,3-BPG, ATP, lactate, nitrocompounds, glutathione, glutamate, because of time delay between blood sampling and end of equilibration, or enlarged distribution space including interstitial fluid and is useful for O2 uptake in the lungs. Under discussion for therapy are the affinity-increasing 5-hydroxymethyl-2-furfural (5-HMF), erythropoiesis stimulating substances like erythropoietin, and methylene blue against MetHb formation.

Subtle case of dapsone-induced methaemoglobinaemia

Methaemoglobinaemia is a rare disease that is typically caused by a medication or other exogenous agent, with dapsone being the most common. It occurs when the concentration of methaemoglobin rises via ferrous haeme irons becoming oxidised to the ferric state, which shifts the oxygen dissociation curve to the left. The net result of an elevated methaemoglobin concentration is functional anaemia and impaired oxygen delivery to tissues. At lower blood levels, this can cause symptoms such as cyanosis, lethargy, headache and fatigue, whereas at higher levels it can be fatal. Here we discuss a subtle case of dapsone-induced methaemoglobinaemia presenting as subacute mental status changes and apparent hypoxia, thus highlighting the association between methaemoglobinaemia and dapsone. This case demonstrates the importance of thorough medication reconciliation and maintaining a broad differential diagnosis, while also recognising the significance of conflicting data and their implications for the workup.

Hemoglobin Non-equilibrium Oxygen Dissociation Curve

Abnormal hemoglobins can have major consequences for tissue delivery of oxygen. Correct diagnosis of hemoglobinopathies with altered oxygen affinity requires a determination of hemoglobin oxygen dissociation curve (ODC), which relates the hemoglobin oxygen saturation to the partial pressure of oxygen in the blood. Determination of the ODC of human hemoglobin is typically carried out under conditions in which hemoglobin is in equilibrium with O2 at each partial pressure. However, in the human body due to the fast transit of RBCs through tissues hemoglobin oxygen exchanges occur under non-equilibrium conditions. We describe the determination of non-equilibrium ODC, and show that under these conditions Hb cooperativity has two apparent components in the Adair, Perutz, and MWC models of Hb. The first component, which we call sequential cooperativity, accounts for ∼70% of Hb cooperativity, and emerges from the constraint of sequential binding that is shared by the three models. The second component, which we call conformational cooperativity, accounts for ∼30% of Hb cooperativity, and is due either to a conformational equilibrium between low affinity and high affinity tetramers (as in the MWC model), or to a conformational change from low to high affinity once two of the tetramer sites are occupied (Perutz model).

Relating oxygen partial pressure, saturation and content: the haemoglobin–oxygen dissociation curve

Key PointsIn clinical practice, the level of arterial oxygenation can be measured either directly by blood gas sampling to measure partial pressure (PaO2) and percentage saturation (SaO2) or indirectly by pulse oximetry (SpO2).This review addresses the strengths and weaknesses of each of these tests and gives advice on their clinical use.The haemoglobin–oxygen dissociation curve describing the relationship between oxygen partial pressure and saturation can be modelled mathematically and routinely obtained clinical data support the accuracy of a historical equation used to describe this relationship.Educational AimsTo understand how oxygen is delivered to the tissues.To understand the relationships between oxygen saturation, partial pressure, content and tissue delivery.The clinical relevance of the haemoglobin–oxygen dissociation curve will be reviewed and we will show how a mathematical model of the curve, derived in the 1960s from limited laboratory data, accurately describes the relationship between oxygen saturation and partial pressure in a large number of routinely obtained clinical samples.To understand the role of pulse oximetry in clinical practice.To understand the differences between arterial, capillary and venous blood gas samples and the role of their measurement in clinical practice.The delivery of oxygen by arterial blood to the tissues of the body has a number of critical determinants including blood oxygen concentration (content), saturation (SO2) and partial pressure, haemoglobin concentration and cardiac output, including its distribution. The haemoglobin–oxygen dissociation curve, a graphical representation of the relationship between oxygen satur­ation and oxygen partial pressure helps us to understand some of the principles underpinning this process. Historically this curve was derived from very limited data based on blood samples from small numbers of healthy subjects which were manipulated in vitro and ultimately determined by equations such as those described by Severinghaus in 1979. In a study of 3524 clinical specimens, we found that this equation estimated the SO2 in blood from patients with normal pH and SO2 >70% with remarkable accuracy and, to our knowledge, this is the first large-scale validation of this equation using clinical samples. Oxygen saturation by pulse oximetry (SpO2) is nowadays the standard clinical method for assessing arterial oxygen saturation, providing a convenient, pain-free means of continuously assessing oxygenation, provided the interpreting clinician is aware of important limitations. The use of pulse oximetry reduces the need for arterial blood gas analysis (SaO2) as many patients who are not at risk of hypercapnic respiratory failure or metabolic acidosis and have acceptable SpO2 do not necessarily require blood gas analysis. While arterial sampling remains the gold-standard method of assessing ventilation and oxygenation, in those patients in whom blood gas analysis is indicated, arterialised capillary samples also have a valuable role in patient care. The clinical role of venous blood gases however remains less well defined.

Adaptation to anemia in hemoglobin E-β thalassemia

Hemoglobin E β thalassemia is the commonest form of severe thalassemia in many Asian countries. Its remarkably variable clinical phenotype presents a major challenge to determining its most appropriate management. In particular, it is not clear why some patients with this condition can develop and function well at very low hemoglobin levels. Here, we demonstrate that patients with hemoglobin Eβ thalassemia have a significant decrease in the oxygen affinity of their hemoglobin, that is an increased P50 value, in response to anemia. This may in part reflect the lower level of hemoglobin F in this condition compared with other forms of β thalassemia intermedia. The ability to right-shift the oxygen dissociation curve was retained across the spectrum of mild and severe phenotypes, despite the significantly higher levels of hemoglobin F in the former, suggesting that efforts directed at producing a modest increase in the level of hemoglobin F in symptomatic patients with this disease should be of therapeutic value.